Solid state ophthalmic medication delivery method

ABSTRACT

A method of delivering a medicament to the eye in solid form is described. The duration of miotic, mydriatic or other pharmacological activity is prolonged by the direct insertion of solid dosage forms of pharmacologically active compounds in the cul-de-sac of the conjunctiva.

United States Patent [191 Haddad et al.

1 1 Mar. 11, 1975 1 SOLID STATE OPHTHALMIC MEDICATION DELIVERY METHOD[76] Inventors: Heskel M. Haddad, 1200 Fifth Ave.,

New York, NY. 10029; Spiro P. Loucas, 16 Toni Ct., Plainview, NY. 11803[22] Filed: Jan. 22, 1974 [21] App]. No.: 435,475

Related US. Application Data [63] Continuation of Bar. No. 246,661,April 24, 1972.

[52] U.S. Cl 424/22, 128/260, 424/14, 424/16, 424/19, 424/180, 424/273,424/361, 424/362 [51] Int. Cl A6lk 27/12 [58] Field of Search 128/260;424/14, 16, 1922, 424/180, 361, 362, 273

OTHER PUBLICATIONS lakovlov, Vistn. Oftal, Nov.-Dec., 1966, pp. 40-42,

The Use of Pilocarpine in a Polyvinyl Alcohol Film for the Treatment ofGlaucomators. Krishna et al., Am. .I. Ophthal 57; 94-106, (1964),Polyvinyl Alcohol as an Opthalmic Vehicle.

Maichuk, Antibiotik 112(5); 432-435. 1967). Polyvinyl Alcohol Films withAntibiotics in the Therapy of Lye Infections.

Anderson et al., Am. .I. Ophthal 51; 1200-1203, (1961), Tissue Responseto Polyvinyl Alcohol lmplants in Rabbits.

Haas et al., Am. J. Ophthal 54; 21-23. (1962), The Effect ofMethylallulose on Responses to Solutions of Piloarpine.

Dohlman et al., Annals. Ophthal, Oct, 1972, pp. 823-832, A New Ocularlnsert Device for Continuous Constant Rate Delivery of Medication to theEye. Loucas et al., J. Pharm. Sci. 61(6), pp. 985-986, June, 1972,Solid-State Ophthalmic Dosage Systems in Effecting Prolonged Release ofPilocarpine in the Cul de Sac.

Haddad, et al., Bull. et Mem. Soc. Fr. Opthalm. 84; 621-624, (1971), LesDerives de lAcide Polyuronique Prolongeant 1e Transport de laPilocarpine.

Primary Examiner-Shep K. Rose Attorney, Agent, or Firm-Fitzpatrick,Cella, Harper & Scinto 13 Claims, 3 Drawing Figures SOLID STATEOPHTHALMIC MEDICATION DELIVERY METHOD This is a continuation applicationof Ser. No. 246,661, Filed Apr. 24, I972.

BACKGROUND OF THE INVENTION This invention relates to a method ofdispensing drugs to the eye over a prolonged period of time.

At the present time, drugs of various kinds are frequently employed inophthalmic practice for the treatment of eye diseases. Since these drugsare rapidly excreted from the body or diffuse from any site of localapplication, repeated or numerous administration of the drug during thecrucial period is generally necessary. Therapeutic substances may beintroduced into the eye by various methods. The methods generally usedare instillation into the conjunctiva] sac, subconjunctival injection,iontophoresis, systemic administration and direct injection into theglobe itself. The most common route is by instillation into theconjunctival sac in the form of drops or ointments. In this method,drugs enter the eye largely through the cornea but to be effective, inmany cases, the application of the drug must be substantiallycontinuous. At the present time, it is not possible to obtain continuousdelivery of a given drug through the use of drops or ointme'nts eventhough they are applied at intervals during a given period. Periodicapplication of such dosage forms generally results in the eye receivinga large but uncertain amount of the drug at the moment it is applied,but the drug is washed away rapidly by tears, thus leaving the eyewithout medication until the next application. For example, personssuffering from glaucoma, a symptomatic condition characterized by anincrease in intraocular pressure, must use eyedrops in large quantitiesand at frequent intervals in order to maintain the base pressure below areasonable level. Pilocarpine is generally used in the treatment ofglaucoma, but frequent administration is required due to the fact thatthe hypotensive action of the drug is not of long duration. Thus, therestill remains a need to find better methods of delivering drugs to theeye so as to obtain the maximum effect from the drug without the needfor frequent administration.

One method which has been proposed for the treatment of acute glaucoma,for example, is to deliver the drug to the eye enclosed in a polyvinylmembrane. This method was proposed by Vropaeva & Indeikin in Oftal; Zh.,24: 543 (no. 7) 1969. The membrane containing the drug is applied to theeyelid. However, it was found that the inclusion of the drug in amembrane did not increase the effectiveness of the drug in the generaltreat ment of acute attacks of glaucoma. An additional drawback is theneed to remove the membrane which contains the drug from the eye aftereach application.

U.S. Pat. No. 3,618,604 describes an ocular insert which is used todispense drugs to the eye. The insert is comprised of a polymericmaterial which is insoluble in tear liquid, the body of which containsthe drug. The drug is then dispensed to the eye by diffusion through thepolymeric material. This method has an inherent disadvantage in that theinsert must be removed from the eye each time after application of thedrug. In addition, the polymeric insert must be so fashioned that itwill not irritate the sensitive tissues of the eye.

U.S. Pat. No. 3,630,200 describes an ocular insert made up of an innercore having an affinity for a given drug and a soft hydrophilic outerlayer. US. Pat. No. 3,626,940 also describes an ocular insert fabricatedfrom polymeric materials, but the insert contains a magneticallyattractable substance to permit insertion and removal of the insert bymagnetic means. Thus, each of the drug dispensing methods described inthe above patents requires removal of the insert after each applicationof the drug.

Other methods include the use of vehicles such as methylcellulose in thepreparation of ophthalmic solutions because of the apparent ability ofthis compound to prolong the action of medicaments which have beendissolved in such solutions. Although the use of methylcellulosesolutions prolongs the action of the medicament, frequent application ofeyedrops made from such solutions is still required in order to bring asufficient quantity of the drug in contact with the eye. Other agentshave been added to ophthalmic solutions for the purpose of prolongingthe effect of the drug, but each of these methods requires the use ofsolutions which must be placed in the eye at frequent intervals.

The object of the present invention is to provide a method of deliveringa therapeutic drug to the eye in solid form which results in acontinuous controlled release of the medicament and obviates the needfor frequent administration of the drug.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relatesto a method of treating diseases of the eye which comprises delivering amedicament in solid form to the eye. The drug, in the form of a disc,pellet, flake, wafer, etc., is placed in the culde-sac of theconjunctiva between the eyeball and the eyelid. While the disc can beinserted under either the upper lid or the lower lid, it is preferred toplace the disc under the lower lid. Once the disc is in place, the drugdisintegrates slowly causing it to be released into the tear fluids. Thedrug is transported to the eyeball by the flow of tear fluid or by theblinking action of the eyelids. A slow diffusional process controls therate of loss of the drug from its solid matrix; thus, the drug is heldin reserve and is available for prolonging the duration of a desiredpupillary response. Due to the slow diffusional process, a means is thusprovided for controlling the release of a given drug from its dosageform in which availability for absorption from the cul-de-sac is moreuniform than is the case with ophthalmic solutions containing the drugs.Thus, a single disc can provide the complete ophthalmic dosagerequirement for a particular time period depending upon theconcentration of the drug in a given disc. Moreover, frequent repeatedapplications of the drug are unnecessary, which is not the case withsolutions and ointments. For the purpose of lessening any irritationwhich may result from the initial contact of the solid with the eye, thesolid may be dipped in an isotonic solution which causes the solid toassume a semi-plastic consistency. Generally, physiological saltsolutions are suitable for this purpose.

Any drug normally used to treat diseases of the eye and the surroundingtissues can be employed which is a solid or can be made into a solidderivative. Also, within the comtemplation of the present invention isthe use of drugs which will pass through the eye or the tissuesurrounding the eye into the bloodstream, but which may not be used intreatment of the eye itself.

Some examples of drugs used in ophthalmic therapy which may be employedin the present invention are: anti-infectives: such as antibiotics,including tetracycline, chlortetracycleine, bacitracin, neomycin,polymyxin, gramicidin, oxytetracycline, chloramphenicol, anderthromycin; sulfonamides, including sulfacetamide, sulfamethizole, andsulfisoxazole; antivirals, including idoxuridine; and otheranti-infectives including nitrofurazone and sodium propionate;antiallergenics such as antazoline, methapyrilene, chlorpheniramine,

pyrilamine and prophenpyridamine; antiinflammatories such ashydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, prednisolone2l-phosphate and prednisolone acetate; decongestants such asphenylephrine, naphazoline, and tetrahydrazoline; miotics andanticholinesterases such as pilocarpine, eserine salicylate, carbachol,diisopropyl fluorophosphate, phospholine iodide, and demacarium bromide;mydriatics such as antropine sulfate, cyclopentolate, homatropine,scopolamine,

tropicamide, eucatropine, and hydroxyamphetamine and sypathomimeticssuch as epinephrine. The drugs can be in various forms such as unchargedmolecules, componenets of molecular complexes, or nonirritating,pharmacologically acceptable salts, such as the hydrochloride,hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate,tartrate, salicylate, salts of polyuronic acids such as alginic acid,galactouronic acid and glucouronic acid, and salts prepared fromcarboxymethylcellulose. Furthermore, simple derivatives of the drugssuch as ethers, esters, amides, etc., which have desirable retention andrelease characteristics but which are easily hydrolyzed by body pH,enzymes, etc. can be employed. The amount of drug used to make up thesolid dosage form will vary widely depending upon the particular drug,the desired therapeutic effect, and the time span for which the soliddosage form will be used There is no critical upper limit on the amountof the drug used since the solid dosage is intended to provide thecomplete dosage requirement for a given period. The lower limit willdepend on the activity of a given drug and its rate of diffusion in thetear fluids. Therefore, it is not practical to define a particular rangefor a therapeutically effective amount to be used to make up the soliddosage. However, generally about 1-50 mg. will be employed in the usualsolid form, depending upon the particular drug employed. The preferredrange is from about 1-10 mg.

The solid dosage form can be prepared by any conventional method used toprepare discs, pellets, wafers, etc., from solids. One method, forexample, involves dissolving the medicament in a solvent such as water,placing the solution in a suitable container or vessel and removing thesolvent by evaporation. Where desired, the semi-solid mass left uponpartial evaporation can be sectioned into the desired shape by means ofvarious size cutting tools. The solid is then dried to ensure theremoval of all of the solvent. In this manner, it is possible to varythe dimensions ofa respective dose by simply replacing the size of thecutting tool or changing the volume of the liquid used in preparation ofthe disc. The disc can be fabricated in any convenient shape, keeping inmind that it must be comfortably retained in the cul-de-sac of the eye.The shape, however, must not have sharp, jagged or rough edges which mayirritate the sensitive tissues of the eye. The

actual shape used presents little problem to eye tissue since theinitial form is changed upon coming into contact with the eye fluids.The solid form of the drug may be a disc, pellet, flake, etc.; it can beconcave, convex, rectangular, etc. The original shape of the solid drugform is not of critical importance. The actual size of the solid dosageform will vary widely. The lower limit will be governed by the amount ofthe particular drug to be applied to the eye to obtain the desiredophthalmic response. The upper limit will be governed by the smallestsized solid which can be conveniently inserted into the cul-de-sac.Generally, the solid form will be about 1-8 mm. in length, about 1-4 mm.in width, having a thickness of about 0.21 mm. The preferred shape is adisc having a thickness of about 0.3 mm., a diameter of 3-7 mm., and aweight of about 3.0-8 mg.

Although the duration of the pharmacological effect of the drug in theeye will depend upon the particular drug employed and the amount used,solid form delivery of the drug generally results in a pupillaryresponse of up to 7-8 hours in the animal and longer in humans.

Those compounds which are normally solids may be delivered in the formof a disc or pellet, etc., without the aid of an additive. Thosecompounds which are normally liquid may be used in the form of apharmacologically acceptable solid derivative. Also contemplated is theuse of a diluent or vehicle in conjunction with the solid dosage form.Suitable vehicles include, for example, methylcellulose,hydroxypropylmethylcellulose, diethylaminoethylcellulose,polyvinylpyrrolidone and pharmacologically acceptable cationic oranionic resms.

The treatment of eye diseases by delivering the medicament directly tothe cul-de-sac of the eye in solid form has general application tovarious diseases of the eye. Any condition where prolonged drugadministration is required may be treated in this manner. For example,it is possible to treat in this manner such eye disorders as uveitis,glaucoma, diseases of the cornea such as, for example, purulentkeratitis, herpes simplex keratitis, herpes zoster, acne rosacea,interstitial keratitis, and the like, diseases of the orbit such asexophthalmas and periostitis and diseases of the conjunctiva such asmucopurulent conjunctivitis and ophthalmia. The present mode of drugdelivery may also be used when postoperative treatment is required suchas after retinal and cataract surgery.

An additional disadvantage related to the use of solutions of drugs inthe treatment of diseases of the eye is the instability of most drugs insolution. Drug solutions generally contain a preservative to preventbacterial growth. The pH of eye fluids is about 7.4 while the pH ofcommercial pilocarpine solutions is about 5.3-5.5. It is known thatacidic solutions tend to cause discomfort to the eye. The administrationof the drug in solid form, however, circumvents the problems relating tostability and eye discomfort since the drug in solid form is stable foran indefinite period.

In a specific example of the method of delivering a drug to thecul-de-sac in solid form, in accordance with the present invention,pilocarpine is prepared in the form of a disc and used to treat thesymptoms of glaucoma. Glaucoma is a clinical condition which ischaracterized by an increase in intra-ocular pressure. The tension whichis associated with chronic simple glaucoma requires careful study andrepeated observation. In cases of chronic simple glaucoma, miotictreatment is generally instituted. The most commonly used miotic ispilocarpine which is administered several times a day. A solution ofabout 0.5-4 percent is used in early cases, but stronger solutions areused when necessary'to control the condition. Eserine can be usedgenerally in an 0025-1 .0 percent solution if necessary and, in certaininstances, stronger cholinergic drugs such as echothiophate iodide(phospholine iodide) may be employed.

In treating glaucoma, pilocarpine is generally administered in the formof an aqueous solution, but it may also be administered in the form ofan ointment or by injection. The eye drops commonly used to make up thesolution generally consist of an aqueous solution of pilocarpinehydrochloride. The present inventors have found that delivery of thedrug, pilocarpine in the present example, to the cul-de-sac of the eyein the form of a solid disc provides a means for controlling the releaseof the drug from a given dosage form. The availability of the drug forabsorption from the cul-de-sac is more uniform than that obtained frominorganic salt type ophthalmic solutions.

The effectiveness of the administration of the drug in solid form isillustrated by the following example. The acid salts used in the exampleare prepared by conventional methods used to prepare acid addition saltsfrom compounds containing a base nitrogen.

EXAMPLE 1 A. Preparation of ophthalmic solid dosage forms a. Pilocarpinealginate ophthalmic discs are prepared by dissolving pilocarpinealginate powder (7 percent w/v) in a small quantity of sterile waterwith stirring. The solution is placed in a flat-bottom petri dish andevaporated under reduced pressure at 30C. in a thermostatic water bathassembly. When the colloidal solution reaches a semi-solid consistency,the mass is sectioned into circular flakes (0.3 mm. thickness, 3-7 mm.diameter, 3.1-7.8 mg.) by means of various size trephines and thesections are dried to the point of solidification at 30C. The solid isdried for an additional 24 hours at room temperature and the discs areremoved and stored in light-resistant containers.

b. Pilocarpine hydrochloride A disc was prepared in the same manner asin (a) above using 14.7 mg. of pilocarpine hydrochloride and 100 mg. ofmethylcellulose 4000 cps in sterile water for injection. A disc weighing4.6 mg. was obtained.

c. Pilocarpine alginate A disc was prepared in the same manner as in (a)above using 22 mg. of pilocarpine alginate and 0.23 mg. ofmethylcellulose in sterile free water for injection. A disc weighing22.23 mg. was obtained.

d. Pilocarpine A disc was prepared as in (a) above using 4 mg. ofpilocarpine. A disc weighing 4 mg. was obtained.

B. Preparation of ophthalmic solutions a. Pilocarpine alginate (3.34percent w/v) solution was prepared from sterile Sorensen phosphatebuffer stock solutions mixed in varying proportions to give a final pHof 6.14. The solution was adjusted for toxicity with sodium chloride.

b. Pilocarpine hydrochloride solution (2.00 percent w/v) in the presenceof methylcellulose 4000 cps required to adjust the viscosity to that ofthe alginate in a) above (72 cps, Brookfield viscosimeter, model LVT,25C.) was prepared from sterile Sorensen phosphate buffer stocksolutions mixed in varying proportions to give final pH of 6.14 andadjusted for toxicity with sodium chloride.

Preparation A l. Pilocarpine alginate Pilocarpine free base (5 g.) andalginic acid powder (5 g.) are mixed together in 50 ml. of sterile,distilled water with stirring. The mixture is heated in a water bath at50C. and the stirring is continued for 1 hour. The resulting gel iscooled to room temperature and the stirring is continued for 24 hoursunder reduced light. The mixture is then diluted to 100 ml. withdistilled water and the resulting solution is stirred for 12 hours atroom temperature. The solution is then transferred toa dessicator-wate rbath assembly and evaporated to dryness under reduced pressure at 30C.The dry powder left upon removal of the water is used directly toprepare the disc and the solution of pilocarpine alginate.

Albino male rabbits are allowed to equilibrate under constant conditionsof illumination for 24 hours prior to treatment with liquid and soliddosages of pilocarpine.

Each solution is delivered from a micrometer syringe (0.075 ml.) intothe lower cul-de-sac of one eye. Aqueous alginic acid or aqueoushydrochloric acid is placed in the other eye as a control. The disc issoaked in isotonic sodium chloride solution and then deposited into thelower cul-de-sac with the aid of forceps. The alginic acid andmethylcellulose disc is used as a control. The size of each pupil ismeasured just before the test drug is applied by means of a Optiker Ryerpupillary gauge fixed at a distance of 6 inches from the globe. Duringmeasurement, the animals are confined in a wooden box which providesfree head and neck motion. Prior to taking measurements, a waitingperiod of one minute is exercised from the time the gauge is broughtwithin the above distance. At specified time intervals, at least sixpupillary diameter readings are made at each point.

Pupillary responses indicate (FIG. 1) that, in the liquid state,pilocarpine alginate exhibits essentially comparable miotic activity aspilocarpine hydrochloride following single dose treatment. No pupillarycontraction is noted in both liquid and solid dose control eyes. Theresults derived from solid pilocarpine alginate deposition show themagnitude of maximum pupil size constriction to be enhanced, withduration of miosis significantly increased over that of both liquiddosage systems. Restoration of normal pupillary diameter for the solidstate dose is observed to occur between 7 and 8 hours in contrast to 3-3rhours for the ophthalmic solution.

In FIG. 2, data for repetitive pilocarpine alginate disc application aregiven. In this study phase, miotic activity is monitored after repeatingthe dose at maximum pupil constriction, 50 percent and percent recoveryof pupillary diameter. Repeating the treatment at 50 percent pupilrecovery gives about a two-fold increase in miotic duration relative toboth single dose deposition and normal pupillary diameter and multipletreatments at the points of maximum constriction. When a second andthird disc is applied at recovery (7 mm.), the behavior is additive withrestoration of pupil size being reached after seven, twelve and aboutseventeen hours.

Overall duration of miosis in the case of triplicate liquid treatments(FIG. 3) at recovery shows that activity derived from solutions ofpilocarpine alginate and pilocarpine hydrochloride methylcellulose isessentially equal. Recovery from the first, second and third dropinstillations is reached at about four, seven and ten hours,respectively.

The availability of the medicament in the cul-de-sac from solid formdoses appears to be more uniform as a consequence of diminisheddiffusion through the gel matrix where the drug is held in reserve incontrast to liquid dosage forms when the dose is immediately released inthe conjunctival fluids. Although the rate of diffusion of the soliddrug will depend on the given drug employed, the concentration of agiven disc can be controlled so as to allow maximum dosage over a givenperiod once the rate of diffusion of a given drug is known. The use ofsolid ophthalmic dosages in the treatment of diseases of the eye is moreeffective than conventional methods and requires less frequentadministration of the drug to produce prolonged physiological activity.

While a preferred embodiment of the present invention has beendescribed, it is apparent that numerous variations and additions may bemade to the invention without departing from the spirit thereof. It isthe intention, therefore, to be limited only by the scope of thefollowing claims:

What is claimed is:

1. A complete ophthalmic dosage of medicament in solid form forinsertion into the cul-de-sac of the eye between the eyeball and lid todispense the medicament to the eye over a prolonged period and leave thecul-de-sac free from tear insoluble residue, comprising a solid matrixof a non-irritating pharmacologically acceptable polyuronic acid orcarboxymethylcellulose salt of a medicament, said matrix adapted to forma gelmatrix after insertion into the cul-de-sac to slowly diffuse saiddosage of medicament to the eyeball, said matrix being free from tearinsoluble carriers.

2. The product of claim 1 in the form of a disc capable of assumingessentially the configuration of the curvature between the eyeball andthe lid.

3. The product of claim 1, wherein the medicament is employed in theform of a salt of a polyuronic acid.

4. The product of claim 3, wherein the polyuronic acid is alginic acid.

5. The product of claim 1, wherein the medicament is a miotic.

6. The product of claim 5, wherein the miotic is selected from the groupconsisting of pilocarpine, cserine and carbachol.

7. A complete ophthalmic dosage of medicament for treating glaucoma, insolid form, for insertion into the cul-de-sac of the eye between theeyeball and lid to dispense the medicament to the eye over a prolongedperiod and leave the cul-de-sac free from tear insoluble residue,comprising a solid matrix of a non-irritating pharmacologicallyacceptable polyuronic acid or carboxymethylcellulose salt of amedicament, said matrix adapted to form a gelmatrix after insertion intothe culde-sac to slowly diffuse said dosage of medicament to theeyeball, said matrix being free from tear insoluble carriers.

8. The product of claim 7, wherein the medicament is employed in theform ofa disc having a marginal outline and cross section adapted toassume essentially the configuration of curvature between the eyeballand the lid.

9. The product of claim 8, wherein the medicament is in the form of adisc having a thickness of about 0.3 mm, a diameter of about 3 to 7 mm,and a weight of about 3-8 milligrams.

10. The product of claim 7, wherein the medicament is present in theform of a salt of a polyuronic acid.

11. The product of claim 10, wherein the polyuronic acid is selectedfrom the group consisting of alginic acid, galactouronic acid andglucouronic acid.

12. The product of claim 7, wherein the medicament is selected from thegroup consisting of pilocarpine, eserine or carbachol.

13. The product of claim 12, wherein the salt is pilocarpine alginate.

1. A COMPLETE OPHTHALMIC DOSAGE OF MEDICAMENT IN SOLID FORM FORINSERTION INTO THE CUL-DE-SAC OF THE EYE BETWEEN THE EYEBALL AND LID TODISPENSE THE MEDICAMENT TO THE EYE OVER A PROLONGED PERIOD AND LEAVE THECUL-DE-SAC FREE FROM TEAR INSOLUBLE RESIDUE, COMPRISING A SOLID MATRIXOF A NON-IRRITATING PHARMACOLOGICALLY ACCEPTABLE POLYURONIC ACID ORCARBOXYMETHYCELLULOSE SALT OF A MEDICAMENT, SAID MATRIX ADAPTED TO FORMA GEL-MATRIX AFTER INSERTION INTO THE CUL-DE-SAC TO SLOWLY DIFFUSE SAIDDOSAGE OF MEDICAMENT TO THE EYEBALL, SAID MATRIX BEING FREE FROM TEARINSOLUBLE CARRIERS.
 1. A complete ophthalmic dosage of medicament insolid form for insertion into the cul-de-sac of the eye between theeyeball and lid to dispense the medicament to the eye over a prolongedperiod and leave the cul-de-sac free from tear insoluble residue,comprising a solid matrix of a non-irritating pharmacologicallyacceptable polyuronic acid or carboxymethylcellulose salt of amedicament, said matrix adapted to form a gel-matrix after insertioninto the cul-de-sac to slowly diffuse said dosage of medicament to theeyeball, said matrix being free from tear insoluble carriers.
 2. Theproduct of claim 1 in the form of a disc capable of assuming essentiallythe configuration of the curvature between the eyeball and the lid. 3.The product of claim 1, wherein the medicament is employed in the formof a salt of a polyuronic acid.
 4. The product of claim 3, wherein thepolyuronic acid is alginic acid.
 5. The product of claim 1, wherein themedicament is a miotic.
 6. The product of claim 5, wherein the miotic isselected from the group consisting of pilocarpine, eserine andcarbachol.
 7. A complete ophthalmic dosage of medicament for treatingglaucoma, in solid form, for insertion into the cul-de-sac of the eyebetween the eyeball and lid to dispense the medicament to the eye over aprolonged period and leave the cul-de-sac free from tear insolubleresidue, comprising a solid matrix of a non-irritating pharmacologicallyacceptable polyuronic acid or carboxymethylcellulose salt of amedicament, said matrix adapted to form a gelmatrix after insertion intothe cul-de-sac to slowly diffuse said dosage of medicament to theeyeball, said matrix being free from tear insoluble carriers.
 8. Theproduct of claim 7, wherein the medicament is employed in the form of adisc having a marginal outline and cross section adapted to assumeessentially the configuration of curvature between the eyeball and thelid.
 9. The product of claim 8, wherein the medicament is in the form ofa disc having a thickness of about 0.3 mm, a diameter of about 3 to 7mm, and a weight of about 3-8 milligrams.
 10. The product of claim 7,wherein the medicament is present in the form of a salt of a polyuronicacid.
 11. The product of claim 10, wherein the polyuronic acid isselected from the group consisting of alginic acid, galactouronic acidand glucouronic acid.
 12. The product of claim 7, wherein the medicamentis selected from the group consisting of pilocarpine, eserine orcarbachol.